The anti-obesity agent fenfluramine (meta-trifluoromethyl N-ethylam-phetamine) may be less subject to human abuse than amphetamine or N-ethyl-amphetamine (NEA) since fenfluramine is not a reinforcer of self-injection responding, or a locomotor-stimulant in animals. Studies using a series of meta-substituted NEAs indicate that the potencies and efficacies of these drugs in the above behaviors are inversely related to meta-substituent size. In vitro studies suggest that the behavioral potencies of the NEAs are related to norepinephrine releases and that drug entry through the noradrenergic neuronal membrane is limited by meta-substituent size. The neurochemical basis for the inverse size-efficacy relationship is less clear but may involve release of norepinephrine, dopamine and serotonin. The proposed studies will evaluate 1) the hypothesis that size-dependency of in vitro norepinephrine release is associated with the neuronal rather than the vesicular membrane, 2) possible variables responsible for the apparent size-indenpendency of in vitro dopamine and serotonin release and 3) the roles of the biogenic amines in the size-dependent behavioral efficacy and potency differences in vivo. The first two goals will be accomplished using amphetamine congener stereoisomerism and drugs which inhibit amine uptake into the vesicular or neuronal compartments (e.g., reserpine, cocaine, benztropine, floxetine). The third will be done using pharmacodynamic studies, preferential depletion of each biogenic amine, uptake inhibitors and receptor blocking agents.